Grignani G, et al. - Trabectedin is an alkylating drug with a distinctive mechanism of action that causes single-strand and double-strand DNA breaks that trigger DNA damage-response pathways, and researchers theorized that poly(ADP-ribose) polymerase 1 (PARP1) inhibitors could be a good partner of trabectedin, after considering the preclinical data. Consequently, in patients with bone and soft-tissue sarcoma, they evaluated the safety, assessed what the recommended phase 2 dose would be, and explored initial signs of activity of combination treatment with trabectedin and olaparib. According to findings, manageable toxicities were demonstrated by trabectedin and olaparib in combination at active dose levels for both drugs. Initial data on antitumor activity were encouraging.

Methods

• For an open-label, multicenter, phase 1b study, patients from the national Italian sarcoma network aged 18 years and older with histologically confirmed bone and soft-tissue sarcoma progressing after standard treatments with Eastern Cooperative Oncology Group performance status of 1 or less were recruited.
• A 24-hour infusion of trabectedin on day 1 and olaparib orally twice a day in 21-day cycles across six dose levels (trabectedin 0.675–1.3 mg/m² every 3 weeks; olaparib 100–300 mg twice a day from day 1 to 21) was administered to patients by using a classic 3+3 design.
• To improve safety and tolerability, intermediate dose levels were permitted.
• The recommended phase 2 dose (the maximum tolerated dose) was determined as the primary endpoint.
• In all patients who received at least one dose of the study drugs, the safety and antitumor activity were evaluated.
• Researchers report the results of the dose-escalation and dose-expansion cohorts.
• The trial is still active but closed to enrolment, with ongoing follow-up for patients who completed treatment.

Results

• With a median follow-up of 10 months (IQR 5–23), a median of four cycles of treatment was given to patients (IQR 2–6; range 1–17 [the patients who received the highest number of cycles are still on treatment]).
• Considering all dose levels, lymphopenia (32 [64%] of 50 patients), neutropenia (31 [62%]), thrombocytopenia (14 [28%]), anemia (13 [26%]), hypophosphatemia (20 [40%]), and alanine aminotransferase concentration increase (9 [18%]) were documented as the most common grade 3–4 adverse events.
• No occurrence of treatment-related life-threatening adverse events or deaths was reported.
• According to data, one (2%) patient interrupted treatment without progression without reporting any specific toxicity.
• Thrombocytopenia, neutropenia for more than 7 days, and febrile neutropenia were documented as dose-limiting toxicities.
• The recommended phase 2 dose was intermediate dose level 4b (trabectedin 1.1 mg/m² every 3 weeks plus olaparib 150 mg twice a day).
• According to Response Evaluation Criteria In Solid Tumors 1.1, a partial response was seen in seven (14%; 95% CI 6–27) of 50 patients.